The research proposed in this competitive renewal seeks to address fundamental, yet unresolved, issues in the disease progression of multiple sclerosis (MS). These studies will utilize advanced MR techniques combined with a highly reproducible computerized volumetric/registration program, and will focus on the resolution of four major experimental issues. In Specific Aim 1, the goal will be to quantitate, over an extended period of time, the total volume of MS brain lesions that are detectable by conventional MR. These results will provide essential information regarding the natural progression of MR-detectable MS lesions, and total lesion volume will be correlated with clinical information, including disease classification and duration, the extent of disability, and neuropsychological testing. The data will be acquired from three carefully selected and monitored cohorts of patients. For two cohorts, one of which displays relapsing-remitting MS, the other of which displays chronic- progressive disease, the proposed experiments will extend our study period from the current 4 years to 9 years. Examination of a third cohort, patients with "probable" MS, will be initiated and conducted over the duration of this proposal. Volumetric analysis will be accomplished using a new concept of "fuzzy connectedness" in images and 3D VIEWNIX software, which has inter- and intraobserver variability of 1.5%. In Specific Aim 2, our attention will focus on the characteristics that distinguish individual brain lesions. For these experiments, we will utilize the quantitative MR technique of magnetization transfer (MT), a technique which can detect subtle structural changes in MS lesions. Individual lesions and their dynamic changes will be analyzed, and subcategorized based on MT measurements. The classification of MS lesions into subcategories will provide an invaluable tool for clinicians. The efficacy of drug treatment can be specifically assessed by observing the result of a particular therapy on a subgroup of MS lesion (i.e., inflammatory vs. demyelinating). In addition, these subcategories will provide the rationale for particular drug therapies or combinations of therapies. Next, Specific Aim 3 will apply MT measurements to quantitate the extent of MR occult lesions (MROL) in MS patients. Importantly, it is unknown whether MS lesions, as observed by conventional MR, evolve from a substrate of normal white matter or from previously damaged white matter (MROL). The detection and quantitation of MROL may be particularly useful in predicting the course and outcome of the disease as well as in the design and results of therapeutic strategies. Finally, Specific Aim 4 is designed to address the implications of spinal cord lesion burden in MS patients. Measurements of spinal cord lesion volume will be correlated with brain lesion volume and clinical measurement to determine what relationship exists between disability measurements, spinal cord disease, and brain MS lesions. These specific aims will provide information with biologic, diagnostic, and therapeutic implications for MS.